The present invention relates to sulfonamide lactam inhibitors of the enzyme Factor Xa which are useful as anticoagulants in the treatment of cardiovascular diseases associated with thromboses.
In accordance with the present invention, novel lactam derivatives are provided which are inhibitors of the enzyme Factor Xa and have the structure I 
including pharmaceutically acceptable salts thereof and all stereoisomers thereof, and prodrugs thereof, wherein
X is defined as:
xe2x80x94(CH2)mxe2x80x94
where m is an integer between 1 and 3 and which may be optionally mono- or di-substituted on 1 to 3 of the methylenes with oxo, lower alky, and aryl;
R1 is selected from alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl and substituted cycloheteroalkyl;
R2 and R3 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, or substituted heteroaryl;
R4, R4a, R5,and R5a are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, hydroxy, alkoxy, 
R6 and R6a are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, cycloheteroalkyl;
R7 and R8 are independently chosen from
xe2x80x94(CH2)nxe2x80x94H
where n is an integer between 1 and 4 and which may be optionally mono- or di-substituted on 1 to 4 of the methylenes with alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and heteroaryl, and which may be optionally substituted with 1 to 4 halogens except on a carbon that is directly bonded to a nitrogen;
or R7 and R8 together with the nitrogen atom to which they are attached may form an optionally substituted cycloheteroalkyl group;
Ra and Rb are the same or different and are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloheteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, substituted alkyl-carbonyl, cycloheteroalkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, alkylaminocarbonyl, substituted alkylaminocarbonyl, dialkylaminocarbonyl, and substituted dialkylaminocarbonyl.
Compounds within the scope of the present invention include compounds of the following formula II 
including pharmaceutically acceptable salts thereof and all stereoisomers thereof, and prodrugs thereof, wherein
Y and Ya are independently a bond, alkyl, alkenyl or alkynyl;
X and Xa are independently
xe2x80x94(CH2)mxe2x80x94
where m is an integer between 1 and 3 and where each methylene group of X may be optionally substituted with oxo, or mono- or di-substituted with lower alkyl or aryl;
Q is a group A or B 
xe2x80x83where
(1) n, p, q and r are each independently 0 to 2, provided that at least one of n, p, q and r is other than zero;
(2) X1 is xe2x80x94Oxe2x80x94, xe2x80x94CR14R15xe2x80x94, xe2x80x94NR14xe2x80x94, or xe2x80x94S(O)txe2x80x94 where t is 1 or 2;
(3) the group B ring system optionally contains one or more double bonds where valence allows; and
(4) optionally fused to the group B ring system is an optionally substituted cycloalkyl ring, an optionally substituted cycloheteroalkyl ring, an optionally substituted heteroaryl ring, or an optionally substituted aryl ring;
R1 and R1a are independently aryl, heteroaryl, cycloalkyl or cycloheteroalkyl any of which may be optionally substituted with one or more groups Z1, Z2 or Z3;
R2, R2a, R3 and R3a are independently selected from
(1) hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, cycloheteroalkyl, or heteroaryl any of which may be optionally substituted with one or more groups Z1a, Z2a or Z3a; or
(2) xe2x80x94C(O)tH, or C(O)tZ6 where t is 1 or 2; or
(3) xe2x80x94Z4xe2x80x94NZ7Z8;
R4, R4a, R4b, R4c, R5, R5a, R5b and R5c are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, hydroxy, alkoxy, 
xe2x80x83any of which may be optionally substituted with one or more groups Z1b, Z2b or Z3b;
R6 and R6a are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or cycloheteroalkyl any of which may be optionally substituted with one or more groups Z1c, Z2c or Z3c;
R7 and R8 are independently chosen from optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl or
xe2x80x94(CH2)nxe2x80x94H,
where n is an integer between 1 and 4 and wherein 1 to 4 of the methylene groups may be optionally mono- or di-substituted with alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and heteroaryl, and which may be optionally substituted with 1 to 4 halogens except on a carbon that is directly bonded to a nitrogen;
or R7 and R8 together with the nitrogen atom to which they are attached may form an optionally substituted cycloheteroalkyl group;
Ra and Rb are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloheteroalkyl, cycloalkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl.
R9 is H, Z3d or when a group R11 is present R9 combines with R11 to form a bond;
R10 is H, Z1f, xe2x80x94Y2xe2x80x94R11, xe2x80x94Y2xe2x80x94N(R11)(Z4xe2x80x94Z9a), xe2x80x94Y2xe2x80x94OR11, xe2x80x94Y2xe2x80x94C(O)R11, xe2x80x94Y2xe2x80x94C(O)OR11, xe2x80x94Y2xe2x80x94OC(O)R11, xe2x80x94Y2xe2x80x94N(Z4xe2x80x94Z9a)xe2x80x94C(O)R11, xe2x80x94Y2xe2x80x94N(Z4xe2x80x94Z9a)xe2x80x94C(O)OR11, xe2x80x94Y2xe2x80x94S(O)tR11 where t is 0 to 2, or xe2x80x94Y2xe2x80x94R12;
Y2 is xe2x80x94(CH2)uxe2x80x94, xe2x80x94Oxe2x80x94(CH2)uxe2x80x94, xe2x80x94C(O)xe2x80x94(CH2)uxe2x80x94, xe2x80x94C(O)Oxe2x80x94(CH2)uxe2x80x94, xe2x80x94OC(O)xe2x80x94CH2)uxe2x80x94 where u is 0 to 3;
R11 when present combines with R9 to form a bond;
R12 is 
R13 is H, Z2f,
R14 is H, Z3f or a group D 
or R13 and R14 combine to form xe2x95x90O or xe2x95x90S;
Z1, Z1a, Z1b, Z1c, Z1d, Z1e, Z1f, Z2, Z2a, Z2b, Z2c, Z2d, Z2e, Z2f, Z3, Z3a, Z3b, Z3c, Z3d, Z3e, Z3f, Z13 and Z14 are each independently
(1) hydrogen or Z6, where Z6 is
(i) alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl or heteroarylalkyl;
(ii) (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) (iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of Z1 through Z3f,
(2) xe2x80x94OH or xe2x80x94OZ6,
(3) xe2x80x94SH or xe2x80x94SZ6,
(4) xe2x80x94C(O)tH, xe2x80x94C(O)tZ6, or xe2x80x94Oxe2x80x94C(O)Z6,
(5) xe2x80x94SO3H, xe2x80x94S(O)tZ6, or S(O)tN(Z9)Z6,
(6) halo,
(7) cyano,
(8) nitro,
(9) xe2x80x94Z4xe2x80x94NZ7Z8,
(10) xe2x80x94Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8,
(11) xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94Z6,
(12) xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94H,
(13) oxo,
Z4 and Z5 are each independently
(1) a single bond,
(2) xe2x80x94Z11xe2x80x94S(O)txe2x80x94Z12xe2x80x94,
(3) xe2x80x94Z11xe2x80x94C(O)xe2x80x94Z12xe2x80x94,
(4) xe2x80x94Z11xe2x80x94C(S)xe2x80x94Z12xe2x80x94,
(5) xe2x80x94Z11xe2x80x94Oxe2x80x94Z12xe2x80x94,
(6) xe2x80x94Z11xe2x80x94Sxe2x80x94Z12xe2x80x94,
(7) xe2x80x94Z11xe2x80x94Oxe2x80x94C(O)xe2x80x94Z12xe2x80x94,
(8) xe2x80x94Z11xe2x80x94C(O)xe2x80x94Oxe2x80x94Z12xe2x80x94,
(9) xe2x80x94Z11xe2x80x94C(xe2x95x90NZ9a)xe2x80x94Z12xe2x80x94, or
(10) xe2x80x94Z11xe2x80x94C(O)xe2x80x94C(O)xe2x80x94Z12xe2x80x94
Z7, Z8, Z9, Z9a and Z10 
(1) are each independently hydrogen or a group provided in the definition of Z6,
(2) Z7 and Z8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups provided in the defintion of Z1 through Z3,
(3) Z7 or Z8, together with Z9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups provided in the defintion of Z1 through Z3, or
(4) Z7 and Z8 or Z9 and Z10 together with the nitrogen atom to which they are attached may combine to form a group xe2x80x94Nxe2x95x90CZ13Z14;
Z11 and Z12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene.
In addition, in accordance with the present invention, a method for preventing, inhibiting or treating cardovascular diseases associated with thromboses is provided, wherein a compound of formula I or II is administered in a therapeutically effective amount which inhibits Factor Xa.
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
The term xe2x80x9calkylxe2x80x9d or xe2x80x9calkxe2x80x9d as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons containing 1 to 20 carbons, preferably 1 to 12 carbons, more preferably 1 to 8 carbons in the normal chain. Examples include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the various additional branched chain isomers thereof. The term xe2x80x9clower alkylxe2x80x9d includes both straight and branched chain hydrocarbons containing 1 to 4 carbons.
The term xe2x80x9calkenylxe2x80x9d as employed herein alone or as part of another group includes both straight and branched hydrocarbons having one or more double bonds, preferably one or two, and being of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons in the normal chain. Examples include 
The term xe2x80x9calkynylxe2x80x9d as employed herein alone or as part of another group includes both straight and branched hydrocarbons having one or more triple bonds, preferably one or two, and being of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons in the normal chain. Examples include 
The terms xe2x80x9csubstituted alkylxe2x80x9d, xe2x80x9csubstituted lower alkylxe2x80x9d, xe2x80x9csubstituted alkenylxe2x80x9d and xe2x80x9csubstituted alkynylxe2x80x9d refer to such groups as defined above having one, two, or three substituents independently selected from the groups listed in the description of T1, T2 and T3.
The term xe2x80x9chaloxe2x80x9d refers to chloro, bromo, fluoro and iodo.
The term xe2x80x9ccycloalkylxe2x80x9d as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds and/or 1 or 2 triple bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 4 to 12 carbons forming the rings. Also included within the definition of xe2x80x9ccycloalkylxe2x80x9d are such rings fused to an aryl, cycloheteroalkyl, or heteroaryl ring and bridged multicyclic rings containing 5 to 20 carbons, preferably 6 to 12 carbons, and 1 or 2 bridges. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, 
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, cyclopentynyl, cyclohexynyl, cycloheptynyl, cyclooctynyl, etc. Cycloalkyl groups may be optionally substituted with one, two or three substituents independently selected from the groups listed in the description of T1, T2 and T3.
The term xe2x80x9carylxe2x80x9d or xe2x80x9carxe2x80x9d as employed herein alone or as part of another group refers to phenyl, 1-naphthyl, and 2-naphthyl as well as such rings fused to a cycloalkyl, aryl, cycloheteroalkyl, or heteroaryl ring.
Examples include 
etc.
Aryl rings may be optionally substituted with one, two or three substituents independently selected from the groups listed in the description of T1, T2 and T3.
The term xe2x80x9ccycloheteroalkylxe2x80x9d as used herein alone or as part of another group refers to 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated rings which includes 1 or more hetero atoms such as nitrogen, oxygen and/or sulfur (preferably 1 to 3 heteroatoms), linked through a carbon atom or an available nitrogen atom. Also included within the definition of cycloheteroalkyl are such rings fused to a cycloalkyl or aryl ring and spiro cycloheteroalkyl rings. One, two, or three available carbon or nitrogen atoms in the cycloheteroalkyl ring can be optionally substituted with substituents listed in the description of T1, T2 and T3. Also, an available nitrogen or sulfur atom in the cycloheteroalkyl ring can be oxidized. Examples of cycloheteroalkyl rings include 
etc. Depending on the point of attachment, a hydrogen may be missing from the nitrogen atom in the above rings.
The term xe2x80x9cheteroarylxe2x80x9d as used herein alone or as part of another group refers to a 5- 6- or 7-membered aromatic rings containing from 1 to 4 nitrogen atoms and/or 1 or 2 oxygen or sulfur atoms provided that the ring contains at least 1 carbon atom and no more than 4 heteroatoms. The heteroaryl ring is linked through an available carbon or nitrogen atom. Also included within the definition of heteroaryl are such rings fused to a cycloalkyl, aryl, cycloheteroalkyl, or another heteroaryl ring. One, two, or three available carbon or nitrogen atoms in the heteroaryl ring can be optionally substituted with substituents listed in the description of T1, T2 and T3. Also an available nitrogen or sulfur atom in the heteroaryl ring can be oxidized. Examples of heteroaryl rings include 
Again, depending on the point of attachment, a hydrogen may be missing from the nitrogen atom in the above rings.
The term xe2x80x9calkoxYxe2x80x9d as employed herein alone or as part of another group includes xe2x80x9calkylxe2x80x9d groups as defined above bonded to an oxygen. Similarly, the term xe2x80x9calkylthioxe2x80x9d as employed herein above or as part of another group includes xe2x80x9calkylxe2x80x9d groups as defined above bonded to a sulfur.
Unless otherwise indicated, the term xe2x80x9csubstituted aminoxe2x80x9d as employed herein alone or as part of another group refers to amino substituted with one or two substituents, which may be the same or different, such as alkyl (optionally substituted), aryl (optionally substituted), arylalkyl (optionally substituted), arylalkyl (optionally substituted), heteroaryl (optionally substituted), heteroarylalkyl (optionally substituted), cycloheteroalkyl (optionally substituted), (cycloheteroalkyl)alkyl (optionally substituted), cycloalkyl (optionally substituted), cycloalkylalkyl (optionally substituted), haloalkyl (optionally substituted), hydroxyalkyl (optionally substituted), alkoxyalkyl (optionally substituted) or thioalkyl (optionally substituted). In addition, the amino substituents may be taken together with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, substituted alkyl, alkoxy, alkylthio, halo, trifluoromethyl, hydroxy, aryl or substituted aryl.
T1, T2 and T3 are each independently
(1) hydrogen or T6, where T6 is
(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, cycloheteroalkyl, (cylcloheteroalkyl)alkyl, heteroaryl, or (heteroaryl)alkyl;
(ii) (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) (iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T1, T2 and T3,
(2) xe2x80x94OH or xe2x80x94OT6,
(3) xe2x80x94SH or xe2x80x94ST6,
(4) xe2x80x94C(O)tH, xe2x80x94C(O)tT6, or xe2x80x94Oxe2x80x94C(O)T6,
(5) xe2x80x94SO3H, xe2x80x94S(O)tT6, or S(O)tN(T9)T6,
(6) halo,
(7) cyano,
(8) nitro,
(9) xe2x80x94T4xe2x80x94NT7T8,
(10) xe2x80x94T4xe2x80x94N(T9)xe2x80x94T5xe2x80x94NT7T8,
(11) xe2x80x94T4xe2x80x94N(T10)xe2x80x94T5xe2x80x94T6,
(12) xe2x80x94T4xe2x80x94N(T10)xe2x80x94T5xe2x80x94H,
(13) oxo,
T4 and T5 are each independently
(1) a single bond,
(2) xe2x80x94T11xe2x80x94S(O)txe2x80x94T12xe2x80x94,
(3) xe2x80x94T11xe2x80x94C(O)xe2x80x94T12xe2x80x94,
(4) xe2x80x94T11xe2x80x94C(S)xe2x80x94T12xe2x80x94,
(5) xe2x80x94T11xe2x80x94Oxe2x80x94T12xe2x80x94,
(6) xe2x80x94T11xe2x80x94Sxe2x80x94T12xe2x80x94,
(7) xe2x80x94T11xe2x80x94Oxe2x80x94C(O)xe2x80x94T12xe2x80x94,
(8) xe2x80x94T11xe2x80x94C(O)xe2x80x94Oxe2x80x94T12xe2x80x94,
(9) xe2x80x94T11xe2x80x94C(xe2x95x90NT9a)xe2x80x94T12xe2x80x94, or (10) xe2x80x94T11xe2x80x94C(O)xe2x80x94C(O)xe2x80x94T12xe2x80x94
T7, T8, T9 and T10 
(1) are each independently hydrogen or a group provided in the definition of T6, or
(2) T7 and T8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T1, T2 and T3, or
(3) T7 or T8, together with T9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T1, T2 and T3, or
(4) T7 and T8 or T9 and T10 together with the nitrogen atom to which they are attached may combine to form a group xe2x80x94Nxe2x95x90CT13T14 where T13 and T14 are each independently H or a group provided in the definition of T6;
T11 and T12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene;
The compounds of formula I can be prepared as salts, in particular pharmaceutically acceptable salts. If the compounds of formula I have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, with amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C1-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane- or p-toluene sulfonic acid. Corresponding acid addition salts can also be formed if the compounds of formula I have an additional basic center. The compounds of formula I having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included.
Preferred salts of the compounds of formula I include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate.
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substituents. Consequently, compounds of formula I can exist in enantiomeric or diastereomeric forms or in mixtures thereof. The processes for preparation can utilize racemates, enantiomers or diastereomers as starting materials. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.
It should be understood that the present invention includes a prodrug forms of the compounds of formula I such as alkylesters of acids or any known prodrugs for lactam derivatives.
The compounds of the instant invention may, for example, be in the free or hydrate form, and may be obtained by methods exemplified by the following descriptions.
The compounds of formula I may be prepared by the exemplary processes described in the following reaction schemes. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples.
The compounds of formula I can be prepared using the reactions shown in the schemes below using techniques known to those skilled in the art of organic synthesis. Additional compounds within formula I can be generated from compounds disclosed in the schemes through conversion of the substituent groups to other functionality by the usual methods of chemical synthesis. In generating compounds of the present invention one skilled in the art will recognize that it may be necessary to protect reactive functionalilty such as hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in reactions. The introduction and removal of protecting groups are well known to those skilled in the art (for example see Green, T. W., xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons 1991).
In one method, lactam II, the preparations of which are know in the literature to those skilled in the art, shall be protected on the nitrogen atom alpha to the carbonyl by the Cbz group to produce lactam III. The Boc and other protecting groups may also be used. Lactam III may then be derivatized by alkylation with appropriately substituted alpha-halo esters such as methyl bromoacetate, methyl 2-bromopropionate, or methyl 2-bromo-2-phenylacetate to yield lactam IV, where X is defined as in structure I. Hydrolysis of the ester with LiOH and the like will give the acid V. 
The coupling of V with various amines to produce product amides can be accomplished using numerous procedures known to those skilled in the art. A suitable example employs ethyl 3-(dimethylamino)propylcarbodiimide hydrochloride (WSC, EDCI) and 1-hydroxybenzotriazole hydrate (HOBt).
The Cbz protecting group can be removed, for example with hydrogen over palladium, to give amine compound VII. Reaction of VII with sulfonyl chlorides in the presence of triethylamine or other base will provide the product VIII. 
Alternatively, the Cbz-protecting group of compound IV can be removed with hydrogen and palladium to give compound IX. This compound can then be sulfonylated to yield compound X, which can be hydrolyzed with lithium hydroxide and the like to produce the acid XI. Compound XI can then be coupled with various amines as described above to yield products of formula VIII. 
In addition to the methods already described, compounds of formula I wherein R2 is other than hydrogen can be prepared as shown in the following scheme. Compounds of formula VIIIa are sequentially treated with a base such as NaH or the like and then with an alkylating agent R2-halogen (for example; methyl iodide, methyl bromoacetate, benzyl bromide and the like) to provide the title compounds. Similarly, compounds of formula VIIIa are treated with an acylating agent, for example methyl chloroformate, to provide the title compounds. 
In a similar fashion, compounds of formula IVa are treated with a base (cesium carbonate and the like) and an alkylating agent such as is methyl iodide to provide compounds of formula IV which are transformed using aformentioned procedures. 
R2 other then Hydrogen may also be introduced by reductive amination procedures. For example, compounds of formula IXa are treated with an aldehyde and a reducing agent such as sodium triacetoxyborohydride to produce compounds of the type IXb. The aldehyde may be attached to a polymer support to provide resin-bound intermediates which can be treated using the other described procedures. Resin cleavage techniques are well known to those skilled in the art. 
In a similar fashion compounds of formula VIIa may be resin bound or functionalized to produce compounds of formula VIIb. 
Preferred compounds of this invention are those of Claim 1 including a pharmaceutically acceptable salt thereof wherein:
X is CH2;
R1 is selected from alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, cycloheteroalkyl, and heteroaryl;
R2 is H, alkyl or substituted alkyl;
R3, R4, R4a, R5, R5a, R6, and R6a are H or alkyl;
R7 and R8 are independently chosen from
xe2x80x94(CH2)nxe2x80x94H
where n is an integer between 1 and 4 and which may be optionally mono- or di-substituted on 1 to 4 of the methylenes with alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and heteroaryl, and which may be optionally substituted with 1 to 4 halogens except on a carbon that is directly bonded to a nitrogen;
or R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted cycloheteroalkyl group;
More preferred compounds of this invention are those of formula I or a pharmaceutically acceptable salt thereof wherein:
X is CH2;
R1 is selected from, substituted alkyl (especially (heteroaryl)alkyl or (aryl)alkyl), substituted alkenyl (especially (heteroaryl)alkenyl or (aryl)alkenyl), substituted alkynyl (especially (heteroaryl)alkynyl or arylalkynyl), substituted cycloalkyl, aryl, cycloheteroalkyl, and heteroaryl;
R2 is H, alkyl or substituted alkyl;
R3, R4, R4a, R5, R5a, R6, and R6a are H.
R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted cycloheteroalkyl group (especially pyrolidine, piperadine, piperazine, morpholine, thiomorpholine or thiazolidine).
More preferred compounds include compounds of formula II wherein
X is CH2;
Y is a bond or alkyenyl (when alkenyl, Y is preferably xe2x80x94CHxe2x95x90CHxe2x80x94, and more preferably 
R1 is aryl or heteroaryl, either of which may be optionally substituted with one or more groups Z1, Z2, Z3 (especially where Z1, Z2 and Z3 are independently halo, cyano, xe2x80x94OH, xe2x80x94OZ6, alkyl, aryl, heteroaryl, or xe2x80x94Z4xe2x80x94NZ7Z8, any of which may be further substituted where valence allows as provided in the definition of Z1, Z2 and Z3);
R2 is H, alkyl, xe2x80x94C(O)tH, xe2x80x94C(O)tZ6, xe2x80x94Z4xe2x80x94NZ7Z8, -(alkyl)-C(O)tH, -(alkyl)-C(O)tZ6, or -(alkyl)-Z4xe2x80x94NZ7Z8;
R3, R4, R4a, R5, R5a, R6, and R6a are H;
Q is a group B;
R9 is H, Z3d or when a group R11 is present R9 combines with R11 to form a single bond;
R10 is H, Z1f, xe2x80x94Y2xe2x80x94R11, Y2xe2x80x94R12 or xe2x80x94Y2xe2x80x94N(R11)xe2x80x94Z4xe2x80x94Z9a;
Y2 is xe2x80x94(CH2)uxe2x80x94 or xe2x80x94C(O)xe2x80x94(CH2)xe2x80x94;
Z3d and Z1f are each independently H, halo, oxo, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, -(alkyl)-cycloalkyl, -(alkyl)-cycloheteroalkyl, -(alkyl)-aryl, -(alkyl)-heteroaryl, xe2x80x94OH, xe2x80x94OZ6, xe2x80x94C(O)tH, xe2x80x94C(O)tZ6, xe2x80x94S(O)tZ6, -(alkyl)-OH, -(alkyl)-OZ6, -(alkyl)-C(O)tH, -(alkyl)-C(O)tZ6, -(alkyl)-S(O)tZ6, xe2x80x94Z4xe2x80x94NZ7Z8, xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94Z6, xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94H, xe2x80x94Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8, -(alkyl)-Z4xe2x80x94NZ7Z8, -(alkyl)-Z4xe2x80x94N(Z10)xe2x80x94Z5Z6, -(alkyl)-Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94H, or -(alkyl)-Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8 any of which may be optionally further substituted where valence allows as provided in the respective definitions of Z3d and Z1f;
R14 is a group D or H, halo, oxo, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, -(alkyl)-cycloalkyl, -(alkyl)-cycloheteroalkyl, -(alkyl)-aryl, -(alkyl)-heteroaryl, xe2x80x94OH, xe2x80x94OZ6, xe2x80x94C(O)tH, xe2x80x94C(O)tZ6, xe2x80x94S(O)tZ6, -(alkyl)-OH, -(alkyl)-OZ6, -(alkyl)-C(O)tH, -(alkyl)-C(O)tZ6, -(alkyl)-S(O)tZ6, xe2x80x94Z4xe2x80x94NZ7Z8, xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94Z6, xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94H, xe2x80x94Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8, -(alkyl)-Z4xe2x80x94NZ7Z8, -(alkyl)-Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94Z6, -(alkyl)-Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94H, or -(alkyl)-Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8 any of which may be optionally further substituted where valence allows as provided in the definition of R14;
Z4 is a bond xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NZ9a)xe2x80x94, xe2x80x94C(O)xe2x80x94C(O)xe2x80x94 or xe2x80x94C(O)Oxe2x80x94; and
Z5 is xe2x80x94C(O)xe2x80x94 or xe2x80x94SO2xe2x80x94.
The most preferred compounds are those of formula I or a pharmaceutically acceptable salt thereof wherein:
X is CH2;
R1 is selected from, optionally substitued heteroaryl, optionally substituted (heteroaryl)alkenyl, optionally substituted aryl or optionally substituted (aryl)alkenyl (especially where the aryl and heteroaryl groups are optionally substituted with one or more halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl);
R2 is H, alkyl or substituted alkyl;
R3, R4, R4a, R5, R5a, R6, and R6a are H;
R7 and R8 together with the nitrogen atom to which they are attached form a cycloheteroalkyl group (especially pyrrolidine) which may be optionally substituted (especially with one or more (amino)alkyl, or (substituted amino)alkyl.
Most preferred compounds include compounds of formula II wherein
X is CH2;
Y is a bond or 
R1 is aryl or heteroaryl, either of which may be optionally substituted with one or more halo, cyano, xe2x80x94OH, xe2x80x94OZ6 (especially alkoxy), optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or xe2x80x94Z4xe2x80x94NZ7Z8;
R2 is H, alkyl, xe2x80x94C(O)tH, xe2x80x94C(O)tZ6, xe2x80x94Z4xe2x80x94NZ7Z8, -(alkyl)-C(O)tH, -(alkyl)-C(O)tZ6, or -(alkyl)-Z4xe2x80x94NZ7Z8,
R3, R4, R4a, R5, R5a, R6, and R6a are H;
Q is a group B;
R9 is H, Z3d or, when a group R11 is present R9 combines with R11 to form a single bond;
R10 is H, Z1f, xe2x80x94Y2xe2x80x94R11 or xe2x80x94Y2xe2x80x94R12;
Y2 is xe2x80x94(CH2)uxe2x80x94 or xe2x80x94C(O)xe2x80x94(CH2)xe2x80x94;
Z3d and Z1f are each independently H, alkyl, heteroaryl, -(alkyl)-cycloheteroalkyl, -(alkl)-Z4xe2x80x94NZ7Z8, xe2x80x94Z4xe2x80x94NZ7Z8, -(alkyl)-Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94Z6, -(alkyl)-Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8, xe2x80x94C(O)tZ6, -(alkyl)-C(O)tZ6, -(alkyl)-OH, -(alkyl)-OZ6, or xe2x80x94S(O)tZ6;
R14 is a group H, -(alkyl)-cycloheteroalkl, -(alkyl)-Z4xe2x80x94NZ7Z8, xe2x80x94Z4xe2x80x94NZ7Z8, -(alkyl)-Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94Z6, -(alkyl)-Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8, xe2x80x94C(O)tZ6, -(alkyl)-C(O)tZ6, -(alkyl)-OH, -(alkyl)-OZ6, xe2x80x94S(O)tZ6 or a group D;
Z4 is a bond xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NZ9a)xe2x80x94, xe2x80x94C(O)xe2x80x94C(O)xe2x80x94, or xe2x80x94C(O)Oxe2x80x94; and
Z5 is xe2x80x94C(O)xe2x80x94 or xe2x80x94SO2xe2x80x94.
The compounds of the present invention are inhibitors of the activated coagulation serine protease known as Factor Xa and thus are useful for the treatment or prophylaxis of those processes which involve activation of the coagulation cascade and especially those which involve the production and/or action of Factor Xa. Thus the compounds of the present invention are useful in the prevention and treatment of all Factor Xa-associated conditions. An xe2x80x9cFactor Xa-associated conditionxe2x80x9d is a disorder which may be prevented, partially alleviated or cured by the administration of an inhibitor of Factor Xa. Such diseases include arterial thrombosis, coronary artery disease, acute coronary syndromes, myocardial infarction, unstable angina, ischemia resulting from vascular occlusion cerebral infarction, stroke and related cerebral vascular diseases (including cerebrovascular accident and transient ischemic attack). Additionally, the compounds are useful in treating or preventing formation of atherosclerotic plaques, transplant atherosclerosis, peripheral arterial disease and intermittent claudication. In addition, the compounds can be used to prevent restenosis following arterial injury induced endogenously (by rupture of an atherosclerotic plaque), or exogenously (by invasive cardiological procedures such as vessel wall injury resulting from angioplasty).
In addition, the inventive compounds are useful in preventing venous thrombosis, coagulation syndromes, deep vein thrombosis (DVT), disseminated intravascular coagulopathy, Kasabach-Merritt syndrome, pulmonary embolism, cerebral thrombosis, atrial fibrillation, and cerebral embolism. The compounds are useful in treating peripheral arterial occlusion, thromboembolic complications of surgery (such as hip replacement, endarterectomy, introduction of artificial heart valves, vascular grafts, and mechanical organs), implantation or transplantation of organ, tissue or cells, and thromboembolic complications of medications (such as oral contraceptives, hormone replacement, and heparin, e.g., for treating heparin-induced thrombocytopenia). The inventive compounds are useful in preventing thrombosis associated with artificial heart valves, stents, and ventricular enlargement including dilated cardiac myopathy and heart failure. The compounds are also useful in treating thrombosis due to confinement (i.e. immobilization, hospitalization, bed rest etc.).
These compounds are also useful in preventing thrombosis and complications in patients genetically predisposed to arterial thrombosis or venous thrombosis (including activated protein C resistance, FVleiden, Prothrombin 20210 elevated coagulation factors FVII, FVIII, FIX, FX, FXI, prothrombin, TAFI and fibrinogen), elevated levels of homocystine, and deficient levels of antithrombin, protein C, and protein S. The inventive compounds may be used for treating heparin-intolerant patients, including those with congenital and acquired antithrombin III deficiencies, heparin-induced thrombocytopenia, and those with high levels of polymorphonuclear granulocyte elastase.
The present compounds may also be used to inhibit blood coagulation in connection with the preparation, storage, fractionation, or use of whole blood. For example, the compounds may be used to maintain whole and fractionated blood in the fluid phase such as required for analytical and biological testing, e.g., for ex vivo platelet and other cell function studies, bioanalytical procedures, and quantitation of blood-containing components. The compounds may be used as anticoagulants in extracorpeal blood circuits, such as those necessary in dialysis and surgery (such as coronary artery bypass surgery); for maintaining blood vessel patency in patients undergoing transluminal coronary angioplasty, vascular surgery including bypass grafting, arterial reconstruction, atherectomy, vascular graft and stent patency, tumor cell metastesis, and organ, tissue, or cell implantation and transplantation. The inventive compounds may also be inhibitors of the activated coagulation serine proteases known as Factor VIIa, Factor XIa, and thrombin and also inhibit other serine proteases, such as trypsin, tryptase, and urokinase. Thus, the compounds are useful for treating or preventing those processes, which involve the production or action of Factor VIIa, Factor XIa, thrombin, trypsin, and/or tryptase. Inventive compounds with urokinase inhibitory activity are useful as metastasis inhibitors in treating cancer. As used herein with reference to the utilities described below other than metastasis, the term xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d encompasses prevention, partial alleviation, or cure of the disease or disorder.
In view of their above-referenced serine protease inhibitory activity, the inventive compounds are useful in treating consequences of atherosclerotic plaque rupture including cardiovascular diseases associated with the activation of the coagulation cascade in thrombotic or thrombophilic states. The inventive compounds with tryptase inhibitory activity are useful as anti-inflammatory agents, in treating chronic asthma, allergic rhinitis, inflammatory bowel disease, psoriasis, conjunctivitis, atopic dermatitis, pancreatis, rheumatoid arthritis, osteoarthritis, septic shock, and chronic inflammatory joint diseases, diseases of joint cartilage destruction, and/or vascular damage due to bacterial and/or viral infections. Additionally, the inventive compounds may be useful for treating diabetic retinopathy or motor neuron diseases such as a amyotrophic lateral sclerosis, progressive muscular atrophy, and primary lateral sclerosis. Additionally, the inventive compounds may a be useful for tissue remodeling diseases and for treating plaque instability and sequelli. In addition, these compounds may be useful for treating fibrotic diseases and conditions, for example, fibrosis, scleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas, and hypertrophic scars.
In addition, the compounds of the present invention are useful in treating cancer and preventing the prothrombotic complications of cancer. In view of their metastasis inhibition activity, the compounds are useful in treating tumor growth, as an adjunct to chemotherapy, and for treating diseases involving metastases including, but not limited to cancer, more particularly, cancer of the lung, prostate, colon, breast, ovaries, and bone. These compounds may also be useful in preventing angiogenesis.
The inventive compounds may also be used in combination with other antithrombotic or anticoagulant drugs such as thrombin inhibitors, platelet aggregation inhibitors such as aspirin, clopidogrel, ticlopidine or CS-747, warfarin, low molecular weight heparins (such as LOVENOX), GPIIb/GPIIIa blockers, PAI-1 inhibitors such as XR-330 and T-686, inhibitors of xcex1-2-antiplasmin such as anti-xcex1-2-antiplasmin antibody and thromboxane receptor antagonists (such as ifetroban), prostacyclin mimetics, phosphodiesterase (PDE) inhibitors, such as dipyridamole or cilostazol, PDE inhibitors in combination with thromboxane receptor antagonists/thromboxane A synthetase inhibitors (such as picotamide), serotonin-2-receptor antagonists (such as ketanserin), fibrinogen receptor antagonists, hypolipidemic agents, such as HMG-CoA reductase inhibitors, e.g., pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, AZ4522, itavastatin (Nissan/Kowa), and compounds disclosed in U.S. provisional applications No. 60/211,594 filed Jun. 15, 2000, and No. 60/211,595 filed Jun. 15, 2000; microsomal triglyceride transport protein inhibitors (such as disclosed in U.S. Pat. Nos. 5,739,135, 5,712,279 and 5,760,246), antihypertensive agents such as angiotensin-converting enzyme inhibitors (e.g., captopril, lisinopril or fosinopril); angiotensin-II receptor antagonists (e.g., irbesartan, losartan or valsartan); and/or ACE/NEP inhibitors (e.g., omapatrilat and gemopatrilat); xcex2-blockers (such as propranolol, nadolol and carvedilol), PDE inhibitors in combination with aspirin, ifetroban, picotamide, ketanserin, or clopidogrel and the like. The inventive compounds are also useful in combination with anti-arrhythmic agents such as for atrial fibrillation, for example, amiodarone or dofetilide.
The inventive compounds may be used in combination with prothrombolytic agents, such as tissue plasminogen activator (natural or recombinant), streptokinase, reteplase, activase, lanoteplase, urokinase, prourokinase, anisolated streptokinase plasminogen activator complex (ASPAC), animal salivary gland plasminogen activators, and the like. The inventive compounds may also be used in combination with xcex2-adrenergic agonists such as albuterol, terbutaline, formoterol, salmeterol, bitolterol, pilbuterol, or fenoterol; anticholinergics such as ipratropium bromide; anti-inflammatory cortiocosteroids such as beclomethasone, triamcinolone, budesonide, fluticasone, flunisolide or dexamethasone; and anti-inflammatory agents such as cromolyn, nedocromil, theophylline, zileuton, zafirlukast, monteleukast and pranleukast.
The inventive compounds may also be useful in combination with other anticancer strategies and chemotherapies such as taxol and/or cisplatin.
The compounds may act synergistically with one or more of the above agents. For example, the inventive compounds may act synergistically with the above agents to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperfusion. Thus, reduced doses of thrombolytic agent(s) may be used, therefore minimizing potential hemorrhagic side effects.
The compounds of this invention may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or quantity of drug to be delivered. Systematic treatment is typically preferred for cancerous conditions, although other modes of delivery are contemplated. The compounds may be delivered orally, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; sublingually; bucally; transdermally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; rectally such as in the form of suppositories; or liposomally. Dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents may be administered. The compounds may be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly in the case of extended release, with devices such as subcutaneous implants or osmotic pumps.
Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The inventive compounds may be orally delivered by sublingual and/or buccal administration, e.g., with molded, compressed, or freeze-dried tablets. Exemplary compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICEL) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g., GANTREZ); and agents to control release such as polyacrylic copolymer (e.g., CARBOPOL 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer""s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquefy and/or dissolve in the rectal cavity to release the drug.
The effective amount of a compound of the present invention may be determined by one of ordinary skill in the art. The specific dose level and frequency of dosage for any particular subject may vary and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. An exemplary effective amount of compounds of formula I may be within the dosage range of about 0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg (or from about 1 to about 2500 mg, preferably from about 5 to about 2000 mg) on a regimen in single or 2 to 4 divided daily doses.
The ability of compounds of the present invention to inhibit Factor Xa can be determined using methods well known to those skilled in the art, such as methods that measure FXa amidolytic (Balasubramanian et al., J. Med. Chem. 36:300-303, 1993;Combrink et al., J. Med. Chem. 41:4854-4860, 1998), clotting time (Balasubramanian, N. et al., J. Med. Chem. 36:300-303, 1993) and in vivo models of arterial and venous thrombosis (Schumacher et al., Eur. J. Pharm. 259:165-171, 1994).
General Experimental and Definitions
The following examples and preparations describe the manner and process of making and using the invention and are illustrative rather than limiting. It is to be understood that there may be other embodiments which fall within the spirit and scope of the invention as defined by the claims appended hereto. Abbreviations and terms employed herein are defined below.
brine=saturated aqueous sodium chloride
Dess-Martin periodinane=1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-Benziodoxol-3(1H)-one
DMF=N,N-dimethylformamide
EDCI=1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride.
PS-PB-CHO=1% Cross linked polystyrene with (4-formyl-3-methoxyphenoxy)methyl linker.
PyBOP=(T-4)-(1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinyl-phosphorus(1+)hexafluorophosphate(1xe2x88x92)=Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate
TFA=trifluoroacetic acid
TFFH=Tetramethylfluoroformamidinium hexafluorophosphate.
THF=tetrahydrofuran
WSC=1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride.
Unless otherwise noted all mass spectral data are positive ion spectra.
The following conditions were used for HPLC:
Method 1: columnxe2x80x94YMC S5 C18 ODS 4.6xc3x9750 mm; flowxe2x80x944.0 mL/min.; detection at 220 nm; solventxe2x80x94A=90:10/water:methanol+0.2% phosphoric acid, B=10:90/water:methanol+0.2% phosphoric acid; gradient-linear, 0% B to 100% B over 4 min and hold at 100% B for 1 min.
Method 2: columnxe2x80x94YMC (ODS) S-5, 4.6 mmxc3x9733 mm; flowxe2x80x945.0 mL/min.; detection at 220 nm; solventxe2x80x94A=10% methanol/water+0.2% phosphoric acid, B=90% methanol/water+0.2% phosphoric acid; gradient-linear, 0% B to 100% B over 2 min and 100% B for 1 min.
Method 3: columnxe2x80x94YMC A-ODS S-5, 4.6 mmxc3x9750 mm; flowxe2x80x944 mL/min.; detection at 220 nm; solventxe2x80x94A=90:10 water:methanol, solvent B=10:90 water:methanol (both containing 0.1% trifluoroacetic acid); 0% B to 100% B (4 min linear gradient) and 100% B for 1 min.
Method 4: columnxe2x80x94YMC (ODS-A) S-5, 4.6 mmxc3x9733 mm; flowxe2x80x945 mL/min.; detection at 220 nm; solventxe2x80x94A=10% methanol/water+0.1% TFA, B=90% methanol/water+0.1% TFA; gradient-linear, 0% B to 100% B over 2 min and 100% B for 1 min.
Method 5: columnxe2x80x94YMC (S3 ODS column) 3 mmxc3x9750 mm; detection at 220 nm; flowxe2x80x945 mL/min; solventxe2x80x94A=10% methanol/water+0.1% TFA, B=90% methanol/water+0.1% TFA; linear gradient, 0% B to 100% B over 2 min and 100% B for 1 min.
Method 6: columnxe2x80x94Phenomenex (5 micron ODS column) 4.6 mmxc3x9730 mm; detection at 220 nm; flowxe2x80x945 mL/min.; solventxe2x80x94A=10% methanol/water+0.1% TFA, B=90% methanol/water+0.1% TFA; linear gradient, 0% B to 100% B over 2 min and 100% B for 1 min.
Method 7: columnxe2x80x94Shimadzu VP-ODS, 4.6 mmxc3x9750 mm; flowxe2x80x944 mL/min.; detection at 220 nm; solventxe2x80x94A=10% methanol/water+0.1% TFA, B=90% methanol/water+0.1% TFA; linear gradient, 0% B to 100% B over 4 min and 100% B for 2 min.
Method 8: Luna (5micron ODS column) 2xc3x9730 mm; flowxe2x80x941 ml/min; detection at 220 nm; solventxe2x80x94A=10 mM ammonium acetate in 98% water/acetonitrile; solvent B=10 mM ammonium acetate in 90% MeCN/water; 3 min linear gradient 0%-100% B and 0.4 min hold at 100% B.
Method 9: columnxe2x80x94Waters Xterra, 4.6 mmxc3x9750 mm; flowxe2x80x945.0 mL/min.; detection at 220 nm; solventxe2x80x94A=10% methanol/water+0.2% phosphoric acid, B=90% methanol/water+0.2% phosphoric acid; gradient-linear, 0% B to 100% B over 2 min.
Method 10: columnxe2x80x94YMC S5 C18 ODS 4.6xc3x9750 mm; flowxe2x80x942.5 mL/min.; detection at 220 nm; solventxe2x80x94A=90:10/water:methanol+0.2% phosphoric acid, B=10:90/water:methanol+0.2% phosphoric acid; gradient-linear, 40% B to 60% B over 10 min.